(1) By continuing to develop formal human genetics with special regard to linkage we aim: 1.1 To develop and apply multipoint mapping so as to extract information about gene order that may be less efficiently inferred from 2-point tests, or from n-point tests where coincidences are estimated as nuisance parameters. 1.2 To resolve linkage heterogeneity due to incomplete penetrance. 1.3 To develop kinship mapping of genetic systems. (2) By continuing to exploit research opportunities presented by the unique population of Hawaii and a collaborative population cytogenetics program we aim: 2.1 To develop and apply methods for centromere mapping using trisomies and triploids. 2.2 To determine the segregation pattern of structural chromosomal rearrangements, and specifically whether segregation is distorted. 2.3 To determine recurrence risks following a karyotyped abortion. 2.4 To test for holandric inheritance of sex ratio in interracial crosses. (3) By continuing to develop and validate the methods of genetic epidemiology we aim: 3.1 To use combined analysis of segregation, linkage, and association to infer etiology of diseases associated with markers like HLA, especially multiple sclerosis, insulin-dependent diabetes, and coeliac disease. 3.2 To resolve controversy about sex differences in mutation rate, initially for Menke's disease and the fragile-X syndrome and eventually for other sex-linked diseases. 3.3 To test alternative models in real and simulated data. 3.4 To implement distributed computing in genetic epidemiology.